The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review

Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson’s disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.


Introduction
The number of older adults diagnosed with neurodegenerative disorders is rapidly growing.Neurodegenerative disorders are characterized by progressive neuronal loss and constitute the aftereffect of labyrinthine genetic and environmental interactions [1].Their categorization is based on cardinal clinical manifestations (e.g., neurocognitive or movement disorders), spatial patterns of brain involvement (e.g., frontotemporal, extrapyramidal, temporoparietal neurodegeneration), or molecular pathology (e.g., α-synucleinopathies, β-amyloidoses, Tau-opathies, disorders associated with pathological formations of the TDP-43 protein) [2].The lack of adequate and effective management combined with the economic and psychological burden of neurodegenerative disorders on patients and caregivers highlights the need for early diagnosis and effective preventive strategies [3,4].
However, the remarkable clinical heterogeneity along with the considerable clinicopathological overlap of neurodegenerative disorders often makes their differential diagnosis quite challenging [5].To establish an accurate diagnosis, modern neuroimaging techniques providing both structural (pathological and anatomical information) and functional (data on brain activation) information are often capitalized on.The combination of these techniques allows a comprehensive examination of brain pathology and has-to a certain extent-replaced the need for post-mortem brain studies (autopsies) [6,7].Not only do these techniques serve as an adjunct to the diagnostic process, but they also contribute to the detection of the neuro-anatomical correlations of motor, cognitive, and behavioral changes, progressively becoming an integral part of clinical evaluation and research [8].
It is known that compensatory mechanisms in individuals with neurodegenerative disorders either recruit intact neural circuits of adjacent brain regions or activate existing neural networks to preserve cognitive and motor functioning [9].These compensatory mechanisms co-occur with the onset of neuronal loss in the early stages of neurodegeneration [10].The existence of a crucial breakpoint is hypothesized during the course of neurodegeneration, whereby the early pattern of neural compensation (maintenance of clinical performance) is succeeded by the more typical pattern of neurodegeneration (clinical impairment).This sequence is often captured by functional neuroimaging as increased cerebral perfusion (attributed to the build-up of neurovascular compensatory mechanisms accounting for higher metabolic needs that allow the preservation of normal functions) followed by decreased brain perfusion (subsequent failure of compensatory responses) with progressively greater diminution [11].Among the available modalities, functional near-infrared spectroscopy (fNIRS) may serve as a non-invasive, low-cost, portable, easy-to-use diagnostic tool in the identification of early neurodegenerative alterations and subclinical compensatory responses.Brain activity is quantified in fNIRS by capturing hemodynamic responses.Evidence for both hypo-and hyper-activation (hypo-and hyper-perfusion) has been reported in prodromal disease stages; the latter is suggestive of compensatory responses in which alternate brain networks are recruited to counteract neurodegeneration [12,13].

Functional Near-Infrared Spectroscopy
Functional near-infrared spectroscopy (fNIRS) is an optical, non-invasive neuroimaging technique developed by Jöbsis in 1977 to study the behavior of cytochrome c oxidase in vivo [14].Later, it was found that the application of infrared light in the near range of 700-1300 nm offers good visibility of tissue oxygenation, which laid the foundations for the utilization of this method in the study of animal and human brains [15].fNIRS depends on "neurovascular coupling"; neuronal activation during a task is associated with vasodilation and increased blood flow [16], followed by an increase in the concentration of oxyhemoglobin and a simultaneous decrease in the concentration of deoxyhemoglobin ensue [16].fNIRS uses light rays close to the visible range (or optical window), which are emitted from a light source (source/light-emitting diode) to the skull and are subsequently captured by a photodetector that collects the scattered rays and measures the degree of light attenuation and absorption [17].During this process, chromophores of the neural tissue absorb light more strongly than surrounding tissues [17].The absorption of infrared light as a function of wavelength is different for oxyhemoglobin and deoxyhemoglobin molecules; the detection of changes in the relative concentrations of light-absorbing chromophores allows fNIRS to capture energy metabolism in the brain [16].
The utilization of fNIRS in clinical practice has rapidly increased over the last few decades for the functional study of the human brain.Compared to other functional neuroimaging modalities, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), magnetoencephalography (MEG), and electroencephalography (EEG), fNIRS exhibits several important advantages: the portability of the device (which allows the measurement of brain activity in various settings), its low cost, its high tolerance by patients, its compatibility with other therapeutic devices (e.g., electroencephalogram-EEG), the high temporal resolution of the data obtained (with a maximum sampling rate approaching 100 Hz), and the low interference of head movements with cerebral signals [8,18,19].fNIRS is, therefore, a potentially useful alternative functional neuroimaging technique for diagnostic and rehabilitation purposes related to various acquired or inherited neurological conditions (such as neurodevelopmental syndromes, epilepsy, neurodegenerative diseases, traumatic brain injuries, and strokes), as well as psychiatric disorders (such as mood disorders, developmental disorders, and schizophrenia [20,21]).

Methods
We searched for clinical studies that used fNIRS either alone or in combination with other imaging modalities to obtain task-related and resting-state cortical activation data in patients diagnosed with the following common neurodegenerative entities: MCI, AD, FTD, PD, and ALS.We focused on studies involving both a group of participants with a neurodegenerative disorder and a comparator group of healthy controls (HC).Uncontrolled studies, controlled studies assessing other neurological conditions, non-observational studies (including reviews, meta-analyses, case reports, editorials, commentaries, viewpoints, and so on), study protocols, book chapters, reviews, and studies not published in English were excluded.Two authors (F.D. and I.L.) independently performed the literature search, data extraction, and interpretation.Potential dissensions were resolved by a third author (G.N.).The literature search was conducted in PubMed and Google Scholar.The search terms included "fNIRS" AND ["neurodegenerative diseases" OR "Alzheimer's disease" OR "Parkinson's disease" OR "mild cognitive impairment" OR "amyotrophic lateral sclerosis" OR "frontotemporal degeneration"].

fNIRS in MCI
MCI lies on the normal cognition-dementia continuum of cognitive decline [22,23].The construct of MCI has been specifically designated to describe an early stage of clinically measurable cognitive impairment that, however, does not interfere with the daily activities of an individual [24].Apart from cognitive impairment, greater neuropsychiatric burden and accelerated courses of cognitive decline and conversion into dementia have been related to this minor neurocognitive entity [25][26][27][28].The concept of MCI has both research and clinical applications, allowing physicians to recruit individuals at high risk of progressing to dementia and apply early preventive strategies [3].
A total of 16 articles comparing individuals with MCI and HC were retrieved (Table 1).Ung and colleagues showed greater bilateral prefrontal activation in individuals with MCI during a visuospatial working memory task [29].Moreover, differences were increasingly steeper with increasing task difficulty, leading to the speculation that MCI patients could handle low working memory loads without the need to compensate, but compensatory mechanisms were recruited at higher levels of difficulty.Similarly, Kim and colleagues reported higher activation of the prefrontal cortex in individuals with MCI during a verbal fluency task, suggesting that MCI patients used compensatory mechanisms and required more energy than the HC to perform the same task [30].Yoon and colleagues found greater activation of the right prefrontal cortex in patients with non-amnestic MCI and hypoactivation in those with amnestic MCI during the Stroop test [31].The authors hypothesized that there were active compensatory mechanisms only in the former group.Yang and colleagues reported hypoactivation of the left but not the right prefrontal cortex in MCI individuals during verbal fluency, Stroop, and N-Back tasks [32,33].The authors theorized that only the right prefrontal cortex in those with MCI can recruit existing neural compensatory mechanisms.Finally, Yap and colleagues observed higher (though non-significant) activation of the right prefrontal cortex in individuals with MCI during a verbal fluency task and reached similar conclusions to those reported by Yang and colleagues [34].Overall, these studies support the concept that the prefrontal cortex of individuals with MCI may engage neural compensatory mechanisms to support declining brain functions.The right prefrontal cortex appears to be of crucial importance in this process; the rightward shift of prefrontal recruitment has been suggested to compensate for the loss of the left prefrontal capacity in the course of healthy and pathological aging [35].Disparities between different MCI subtypes are to be expected; however, additional research is required to better understand these differences.
On the other hand, results indicative of the failure of compensatory mechanisms in MCI have been published as well.Yeung and colleagues showed that contrary to the HC, individuals with MCI did not exhibit significant bilateral frontal activation with high working memory load during the 0-, 2-Back task [36].Consequently, the authors suggested a failure of the MCI group to deploy compensatory efforts in response to increasing task demands.Niu and colleagues found decreased activation of the left dorsolateral prefrontal, right supplementary motor, and left superior temporal regions in individuals with MCI during the 0-, 1-Back task [37].The authors deduced that the MCI group failed to recruit sufficient frontotemporal resources for task performance and to show the expected taskrelated activation exhibited by the HC.Similarly, Haberstumpf and colleagues reported that MCI participants exhibited reduced bilateral parietal activation during the clock-hand angle discrimination task, suggesting a failure to recruit compensatory neural mechanisms [38].Moreover, Li and colleagues assessed participants with MCI and HC on the digit verbal span task and reported reduced activation of frontal and bilateral parietal cortices among those with MCI [39].Katzorke and colleagues examined individuals with MCI and HC on the verbal fluency task and found decreased activation of bilateral inferior frontotemporal regions in MCI [40].Uemura and colleagues assessed older adults with amnestic MCI and HC on memory encoding and delayed retrieval and observed reduced bilateral dorsolateral prefrontal activation in the MCI group during the memory retrieval task [41].Finally, Arai and colleagues evaluated participants with amnestic MCI and HC on the verbal fluency task and documented lower activation of the right parietal area in those with MCI [42].
Based on the above, many authors have argued that the lack of hemodynamic responses in the respective cortical areas during specific neuropsychological tasks may serve as early biomarkers of neurodegeneration.Heterogeneity among published studies should most likely be attributed to the involvement of participants with diverse MCI subtypes, different levels of cognitive impairment, and disparate underlying neuropathological alterations.Additional heterogeneity is probably introduced by cognitive assessments, considering that different neuropsychological tasks target different cognitive domains and bring in different cognitive workloads.Consequently, it is almost impossible to compare-let alone synthesize-the results of published articles involving participants with MCI and HC.Future studies are required to create more homogeneous groups of MCI individuals in order to reveal distinct patterns of cortical hyper-or hypoactivation that may reflect each underlying pathology/MCI subtype at different stages of cognitive decline (existing compensatory mechanisms vs. failure of compensatory responses on the grounds of more advanced neurodegeneration. Of note, among the articles retrieved, three focused on functional brain connectivity.Nguyen and colleagues evaluated MCI patients and HC during a resting state and on the oddball, 1-Back, and verbal fluency tasks [43].Individuals with MCI had higher right and inter-hemispheric connectivity than that of the HC during the resting state and lower left and inter-hemispheric connectivity during the verbal fluency task.Moreover, significantly greater inter-hemispheric than intra-hemispheric connectivity was reported in the HC group during the verbal fluency task-no difference between the inter-and intra-hemispheric connectivity was found in the MCI group.Niu and colleagues assessed participants with amnestic MCI and HC during a resting state and reported disrupted dynamic brain connectivity with increased variability in those with MCI [44].Finally, Wang and colleagues examined individuals with MCI and HC during walking tasks [45].Although no differences were detected during the walking-only tasks, connection strength was greater in the HC than in the MCI patients during more difficult dual task (more complex cognitive activities elicited greater differences).Moreover, connection strength changes with escalating difficulty distinguished those with MCI from the HC.Based on the above, functional connectivity evaluated via fNIRS during a resting state and in cognitive and dual (+walking) tasks could contribute to the screening for cognitive impairment.

fNIRS in AD
AD is the most prevalent neurodegenerative disorder, a leading cause of death and healthcare burden; the aging of the global population and the improvement of-and increased access to-healthcare services are expected to cause the prevalence and incidence of this major neurocognitive entity to skyrocket [46][47][48].AD is usually characterized by early prominent episodic memory impairment along with more subtle cognitive deficits in the remaining cognitive domains and a variety of neuropsychiatric manifestations, such as affective and lability symptoms, apathy, and even psychotic manifestations [25,49].The ATN [β amyloid, tau, neurodegeneration] framework has been introduced to define the underlying neurodegenerative alterations of the disorder and tends to displace the traditional clinical diagnostic approach; β amyloid deposition, tau aggregation, and neurodegenerative changes characteristic of AD not only improve its challenging differential diagnosis but also facilitate early identification-even in a preclinical stage-allowing timely interventions and serving research purposes [50][51][52].
The literature search yielded 12 relevant articles (Table 2).Studies comparing participants with AD to HC uniformly report findings of cortical hypoactivation in the former group.Herrmann and colleagues found reduced (dorsolateral prefrontal cortex) and less locally specific activation during the verbal fluency task [53].Zeller and colleagues documented lower activation of the superior parietal cortex during the modified version of the Benton Line Orientation Task [54].Metzger and colleagues showed hypoactivation of frontoparietal areas (such as the dorsolateral prefrontal cortex) and the superior temporal gyrus during the verbal fluency task [55].Li and colleagues reported that patients assessed on the digit verbal span task presented lower activation of frontal regions (frontal pole, orbitofrontal) [56].Arai and colleagues found lower activation of the bilateral frontal and parietal lobes of those with AD during the verbal fluency task [42].Li and colleagues revealed increasingly reduced activation of frontal and bilateral parietal cortices in the course of progression from mild to moderate/severe AD during the digit verbal span task [39].Yap and colleagues observed lower and relatively delayed activation of the left prefrontal cortex during the verbal fluency task [34].Ung and colleagues showed less pronounced bilateral prefrontal activation with minimal signs of increasing activation with increasing difficulty level during a visuospatial working memory task [29].Based on the above, it can be theorized that compensatory mechanisms may exist early in the course of neurodegeneration (early MCI) but are compromised later on (late MCI, dementia stage).MCI patients may be able to handle increasing cognitive load using compensatory mechanisms at first until they reach their cognitive capacity limits for neural compensation due to more severe neurodegeneration.
Alternative parameters were assessed in a number of articles.Niu and colleagues evaluated participants with AD, amnestic MCI, and HC in terms of functional brain connectivity during a resting state [44].The authors found increasingly disrupted dynamic brain connectivity with escalating variability over progression from normal cognition to MCI and AD.Perpetuini and colleagues analyzed the complexity of activation based on multiscale entropy metrics [57].Those with mild AD exhibited increased complexity of activation during delayed free recall in the dorsolateral and medial prefrontal cortex but comparable complexity to that of the HC during the resting state and other episodic memory tasks.Ateş and colleagues revealed that patients with AD may show relative preservation of working memory performance when positive emotional stimuli are used in contrast to the use of neutral or negative emotional stimuli [58].This function was associated with higher activation of the left ventral prefrontal cortex in patients with AD during the positive condition (and not during neutral and negative conditions).Therefore, positive verbal stimuli were suggested to enhance working memory performance among older adults with AD.Finally, two published articles highlighted the potential of combining fNIRS with other modalities-specifically, EEG [56,59].Multimodal evaluation of neurovascular coupling is even more promising in the identification of undergoing neurodegenerative alterations.

fNIRS in FTD
Frontotemporal dementia (FTD) is a major neurocognitive disorder with two common phenotypic presentations: primary progressive aphasia (PPA) with early prominent language impairment and the behavioral variant (bvFTD) with early alterations in emotion, personality, and executive function [60,61].Frontal and/or anterior temporal atrophy in magnetic resonance imaging (MRI) studies or hypometabolism in fluro-deoxy-glucose positron emission tomography (FDG-PET) are imaging markers of bvFTD [62,63].Apart from these presentations, additional entities on the spectrum include FTD with motor neuron disease (MND), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) [61].
Only one relevant article involving HC, individuals with AD, and the behavioral variant of FTD (bvFTD) was retrieved [55] (Table 2).As mentioned above, compared to the HC, the compensatory ability during the verbal fluency task was reduced in AD; however, the pattern of cortical activation (though less pronounced) was similar to that of the HC (frontoparietal areas such as the dorsolateral prefrontal cortex-superior temporal gyrus).On the other hand, the bvFTD pattern was qualitatively different, namely, more frontopolar-without frontoparietal activation.This study provides evidence that compensatory mechanisms may differ between different neurodegenerative diseases.This is an indication of the diverse neuropathophysiological correlates that can be capitalized upon in the challenging distinction of these conditions.

fNIRS in PD
PD is a progressive neurodegenerative disorder of the central nervous system (CNS) marked by cardinal movement manifestations involving resting tremor, rigidity, bradykinesia, and postural instability [64].Autonomic dysfunction, anosmia, and sleep, cognitive, and neuropsychiatric symptoms may occur.PD is associated with the degeneration of dopamine-producing neurons in the pars compacta of the substantia nigra [65].Cytoplasmic inclusions of a-Synuclein-forming Lewy bodies and neurites tend to accumulate within affected neurons [65][66][67].Following AD, it is the most common neurodegenerative disorder, as well as the most prevalent entity among aS-pathies [66].
The analysis of fNIRS data in PD versus HC provides evidence of the capitalization of cognitive resources (especially executive function) for the compensation of locomotor impairments (Table 3).Ranchet and colleagues examined early-stage PD patients and HC during simple and dual walking tasks [68].They found higher activation of the dorsolateral prefrontal cortex during usual walking and during walking while subtracting in PD, supporting that prefrontal activation is potentially compensatory for subcortical dysfunction and deficits in motor automaticity.Shine and colleagues assessed earlystage PD patients and HC using the obstacle negotiation task [69].In their study, greater activation of the prefrontal region was exhibited during and after this task in PD, especially in the case of more challenging obstacles.These results point to the reliance of patients with PD on cognitive resources during more demanding motor situations.Mahoney and colleagues examined patients with Parkinsonian syndromes, individuals with mild Parkinsonian signs, and HC during the postural control task [70].Their findings support that increasing activation of the prefrontal cortex is required in Parkinsonian syndromes in order to retain postural control compared to those with mild Parkinsonian signs and HC.Belluscio and colleagues evaluated PD patients with (PD-FoG) and without freezing of gait (PD-no FoG) and HC on the 2-min turning-in-place task under single-task and dual-task conditions [71].The authors reported higher activation of the prefrontal cortex in the PD-FoG group.They theorized that the involvement of the prefrontal cortex during a challenging motor task in PD implies the increasing need for the recruitment of executive mechanisms in motor tasks with declining motor performance in the course of PD.Pu and colleagues assessed participants with PD-noFOG, PD-FoG, and HC on the sitting toe-tapping task [72].The greater right prefrontal activation in the PD-FoG group once again suggested that PD-FoG patients require additional cognitive resources to compensate for damaged automaticity in locomotor control.This is more pronounced in cases with more severe FoG than in milder cases.
Additional evidence on the implication of frontally mediated operations (most notably, executive function) in the locomotor performance of patients with PD was provided by the studies of Maidan and colleagues.Individuals with PD-FoG and HC were subjected to different walking tasks known to provoke FoG [73].Increased frontal activation was found before and during anticipated (but not unanticipated) turns with FoG.Later, Maidan and colleagues assessed individuals with PD and HC on the obstacle negotiation task [74].Higher prefrontal activation was found in PD before, during, and after the task in both anticipated and unanticipated obstacle negotiation.Finally, Maidan and colleagues investigated older adults with PD and HC on usual walking, dual walking, and obstacle negotiation tasks [75].Higher activation of the prefrontal cortex was reported during the usual walking and obstacle negotiation tasks.The activation was similar to that in the HC during the dual walking tasks.The authors pointed out that pure motor tasks led to increased frontal lobe activation only in the PD group (neural compensation), whereas cognitive operations during dual walking apparently led to increased frontal lobe activation in the HC group as well.
On the other hand, data indicative of the failure of compensatory mechanisms in PD have also been published.Pelicioni and colleagues examined patients with mild to moderate PD and HC on simple walking and three gait adaptability tasks [76].The authors observed that the PD group had greater activation of the premotor cortex during simple walking (compared to the HC) but no increasing activation with escalating task difficulty in the dorsolateral prefrontal cortex (as seen in the HC).Their findings may suggest that people with PD have little premotor cortex and dorsolateral prefrontal cortex capacity beyond what they need for simple walking.A second study by Pelicioni and colleagues evaluated mild to moderate PD patients and HC on the simple choice stepping reaction time task, the inhibitory choice stepping reaction time task, and the Stroop stepping task [77].Reduced activation of the dorsolateral prefrontal cortex, supplementary motor area, and premotor cortex was found during more complex tasks requiring inhibitory control.This finding may reflect subcortical damage with subsequent deficient use of compensatory cognitive and motor resources.Overall, similarly to neurocognitive entities, depending on the severity and exact phenotype of PD (motor, cognitive, neuropsychiatric manifestations, and so on), as well as on the exact demands of the evaluations utilized, heterogeneity is to be expected.Future research ought to tackle these issues by forming more clinically homogeneous groups.
Finally, one article by Hofmann and colleagues assessed PD converters (almost every one of whom was not diagnosed with PD at the time of the examination) and HC using the Trail-Making Test [78].They found reduced activation of the right dorsolateral prefrontal cortex with increasing task difficulty in PD-on the contrary, the HC exhibited increasing activation with escalating task difficulty.Regarding the left dorsolateral prefrontal cortex, increasing activation with escalating task difficulty was reported in both groups.This could be an early and presumably PD-specific pattern of cortical activation.Left dorsolateral prefrontal cortex: Increasing activation with increasing task difficulty in the HC and PD.Right dorsolateral prefrontal cortex: Increasing activation with increasing task difficulty in the HC.Right dorsolateral prefrontal cortex and sensory association cortex: Generally reduced activation during tasks in PD.
A higher cortical activity due to the more complex task is preserved even within the group of PD converters in the left dorsolateral prefrontal cortex.Reduced activation of the right dorsolateral prefrontal cortex despite escalating task difficulty could be an early and presumably specific pattern for conversion into PD.Prefrontal region: Greater activation during and after the task in PD compared to the HC, especially in the case of more challenging obstacles.

These results point to the use of prefrontal activation as a compensatory mechanism in PD.
There is a greater reliance on cognitive resources in more demanding motor situations in patients with PD.
Involvement of the prefrontal cortex in people with PD while performing a challenging task may imply the recruitment of executive function in performing a motor task among individuals with poorer motor performance.

fNIRS in ALS
ALS is a progressive neurodegenerative disorder that mainly affects the upper and lower motor neurons, and about half of the patients present cognitive decline during the course of the disease [79].The worldwide prevalence of ALS is estimated at approximately between four and five patients per 100,000 individuals, whereas its incidence corresponds to about one to two new cases per 100,000 person-years [80].ALS is more common among males, and its prevalence follows an upward trend towards the eighth decade of life [80].The mean survival of ALS patients is estimated between 2 and 4 years for most populations, with the limited available therapeutic options offering only small benefits in terms of survival and clinical progress [80][81][82].
fNIRS data from studies including ALS patients and HC support the involvement of extra-motor networks and hubs in ALS, even in the absence of measurable cognitive impairment (Table 4).Deligani and colleagues found increased functional connectivity in the frontal and right prefrontal regions of the ALS group during the resting state [83].As activity related to constant monitoring for upcoming stimuli has been reported to occur in the resting state, increased connectivity was theorized to be a compensatory mechanism for monitoring deficits.Borgheai and colleagues assessed participants with ALS and HC (matched for age) on an oddball-based dual visual-mental task [84].Significant hemodynamic contrast was observed primarily in the dorsolateral prefrontal cortex (a region critical to working memory processing) of the ALS group.This strengthens speculation that participants with ALS may have extra-motor impairment with prominent attentional and executive deficits affecting workload processing.Ayaz and colleagues evaluated ALS patients and HC on mental tasks targeting attention, executive function, and processing speed [85].The ALS group had higher activation of the lateral and medial prefrontal cortex, as well as the inferior frontal gyrus, during these tasks.These significant differences between ALS and HC in fNIRS measures during all tasks provide an additional metric for the assessment of cognitive decline in these patients as well.In ALS, the activation level was highest at the beginning of a task and decreased with subsequent trials of increasing difficulty; on the contrary, an increase in activation with escalating task difficulty was reported in the HC.The authors suggested that this finding should be attributed to a higher neural cost of task initiation in ALS, while increasing the task's difficulty exceeds the compensatory capabilities in this population.
Kopitzki and colleagues observed no significant difference in homotopic resting-state functional connectivity (rs-FC) between ALS patients and HC [86].However, individuals with ALS displayed an altered correlation between homotopic rs-FC values obtained at different cortical sites when compared to the HC.The altered spatial pattern of correlation in homotopic rs-FC values measured in different non-motor-associated cortical areas highlights the involvement of non-motor areas in ALS.Kuruvilla and colleagues assessed individuals with ALS and HC on two N-back working memory tasks [87].Decreased activation located approximately over the medial prefrontal cortex in both hemispheres was reported in ALS, while cognitive performance was relatively intact.This finding led the authors to conclude that compensatory reorganization and resource reallocation from other cortical regions may occur in ALS in order to meet cognitive demands when prefrontal neurons degenerate.Moreover, unlike in the HC, activation did not increase with escalating task difficulty.Therefore, it was speculated that increasing task difficulty exceeds the compensatory capabilities in ALS patients.

Discussion
This review highlighted that cortical activation as measured with fNIRS is influenced by the underlying neuropathological entity, the degree to which neural networks have been compromised (early, advanced), and the complexity and target of clinical assessments (neuropsychological, motor, and dual tasks).Even among individuals afflicted with the same neurodegenerative disorder, there is a significant heterogeneity in cortical activation patterns.These patterns may reflect either adaptive or maladaptive pathophysiological processes.
Compensatory responses usually occur early in the course of neurodegeneration [10].During the initial stages, patients often maintain a normal or nearly normal level of clinical performance discrepant to the degree of structural compromise [88].In the course of neurodegeneration, the existence of a crucial breakpoint is theorized, whereby the early pattern of normal (or nearly normal) clinical performance is succeeded by the more typical pattern of clinical impairment [11].The earlier stage is dependent on the development and recruitment of neurovascular compensatory mechanisms, whereas the later stage represents the failure of compensatory responses.This sequence is often captured by functional neuroimaging as increased cerebral perfusion (higher metabolic needs required for the preservation of normal functions) followed by decreased brain perfusion (limited metabolic needs due to more severe neurodegeneration) [11].Hemodynamic responses (and, in turn, patterns of cortical activation and neural compensation or degeneration) can be quantified with fNIRS [12,13].
Based on the above, the relative maintenance of cognitive and/or motor functions along with greater hemodynamic responses (hyperactivation) in fNIRS suggest the involvement of compensatory mechanisms [89].Compensatory processes appear to be inversely related to the degree of neurodegeneration (as is apparent in early disease stages), whereas failure of neural compensation (reduced hemodynamic responses-hypoactivation) is predominantly observed at more severe stages [37].The latter is particularly evident when shifting from simple to complex and/or dual tasks, exposing the inability of patients to cope with excess cognitive load and the utter disruption of compensatory responses.
Our findings indicate that the prefrontal cortex of individuals with MCI (with a rightward shift of prefrontal recruitment) may engage neural compensatory mechanisms to support declining brain functions early in the course of the disorder.However, as neurodegeneration progresses, compensatory mechanisms are compromised; therefore, although both cortical hyperactivation and hypoactivation patterns have been revealed in MCI, early AD is consistently characterized by hypoactivation patterns.In other words, MCI patients may be able to handle increasing cognitive load using compensatory mechanisms at first until they reach their cognitive capacity limits for neural compensation due to more severe neurodegeneration or more demanding cognitive tasks.Individuals with different MCI subtypes and levels of cognitive impairment subjected to heterogeneous cognitive assessments (targeting different cognitive domains and bringing in different cognitive workloads) are expected to reveal distinct patterns of cortical activation.Similarly, discrete underlying pathologies are anticipated to introduce heterogeneous activation patterns (with potential implications for their differential diagnosis-see the FTD paradigm).Of note, the analysis of fNIRS data in PD provided evidence of the leveraging of prefrontal cognitive resources (especially executive function) for the compensation of locomotor impairments as well.
The main limitation of this review is the small number of published studies featuring small and often heterogeneous samples of participants.Second, the majority of the studies primarily focused on task-related hemodynamic responses in frontal and prefrontal areas.This tendency of authors to focus primarily on frontal operations and executive function limits the potential value of fNIRS in clinical practice.It is possible that, due to brain plasticity, the mental workload is shifted to other areas of the brain during task performance.One likely area that was not monitored by most studies is the parietal cortex.Future studies ought to include larger and more homogeneous samples, provide more comprehensive evaluations, and report their findings with accuracy and transparency [90,91].fNIRS itself exhibits a number of limitations related to spatial resolution (restricted to the outer cortex), interference of extracranial matter with measurements (muscles, skull, dura, etc.), the lack of standardized processes (implementation and analysis), and the inability to extract absolute hemoglobin concentrations [21].Also, abrupt head movements and misplacement of the diodes may lead to measurement errors (artifacts are not corrected automatically by software) [92].Upcoming technological advancements are expected to optimize this promising technique and establish fNIRS as a useful tool in the fields of research and clinical practice.

Conclusions
Considering the impact of neurodegenerative disorders, it is necessary to develop widely accessible and easily operated tools to overcome early diagnostic challenges [93][94][95].Thanks to its user-friendly nature and compatibility with other functional neuroimaging techniques, fNIRS holds great potential for the diagnostic assessment of early neurocognitive and motor decline.Early detection serves research purposes and facilitates timely intervention, better management, and the minimization of iatrogenic complications [49,96,97].Moreover, the detection of preserved neuroplasticity offers opportunities for personalized rehabilitation, which can address individuals' needs more efficiently.However, further research is needed to integrate fNIRS and determine its exact place in clinical practice.

Table 1 .
fNIRS studies involving older adults with MCI and HC.

Table 2 .
fNIRS studies involving older adults with AD and HC.

Table 3 .
fNIRS studies involving older adults with PD and HC.

Table 4 .
fNIRS studies involving older adults with ALS and HC.

Table 4 .
Cont.Quantitative data are presented as the mean ± standard deviation depending on the data presentation in the respective article; fNIRS: functional near-infrared spectroscopy; ALS: amyotrophic lateral sclerosis; HC: healthy controls; ALSFRS-R: ALS Functional Rating Scale-Revised; CBS: Cognitive Behavioral Screen; DPR: disease progression rate; PBAC: Philadelphia Brief Assessment of Cognition; MoCA: Montreal Cognitive Assessment.